N-piperidinyl- and N-tetrahydropyridinyl-2-anthracenecarboxamides: dopamine receptor subtype specific ligands

ABSTRACT

Disclosed are compounds of the formula: ##STR1## or the pharmaceutically acceptable acid addition salts thereof, wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are the same or different and represent hydrogen, C 1  -C 6  alkyl, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C 1  -C 6  alkoxy, --O 2  CR&#39;, --NHCOR&#39;, --COR&#39;, --SO m  R&#39;, where R&#39; is C 1  -C 6  alkyl and wherein m is 0, 1 or 2; or 
     R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  independently represent --CONR&#39;R&#34;, or --NR&#39;R&#34; where R&#39; and R&#34; independently represent hydrogen or C 1  -C 6  alkyl; 
     R 10  is hydrogen or C 1  -C 6  alkyl; and 
     R represents an aminoalkyl group; 
     which compounds are useful in the treatment of affective disorders such as schizophrenia, depression, Alzheimer&#39;s disease, movement disorders such as Parkinsonism and dystonia, and other disorders which respond to dopaminergic blockade such as substance abuse and obsessive compulsive disorders. Further, compounds of this invention may be useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents.

This application is a continuation of U.S. application Ser. No.08/619,351 filed Mar. 21, 1996, now U.S. Pat. No. 5,703,235.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to anthracenecarboxamide derivatives whichselectively bind to brain dopamine receptor subtypes. More specifically,it relates to N-Aminoalkyl-2-anthracenecarboxamides and topharmaceutical compositions comprising such compounds. It furtherrelates to the use of such compounds in the treatment or prevention ofvarious neuropsychochological disorders such as schizophrenia and othercentral nervous system diseases.

2. Description of the Related Art

The therapeutic effect of conventional antipsychotics, known asneuroleptics, is generally believed to be exerted through blockade ofdopamine receptors. However, neuroleptics are frequently responsible forundesirable extrapyramidal side effects (EPS) and tardive dyskinesias,which are attributed to blockade of D₂ receptors in the striatal regionof the brain. The dopamine D₃ receptor subtype has recently beenidentified (Sokoloff et al., Nature, 347: 146 (1990). Its uniquelocalization in limbic brain areas and its differential recognition ofvarious antipsychotics suggest that the D₃ receptor may play a majorrole in the etiology of schizophrenia. Selective D₃ antagonists may beeffective antipsychotics free from the neurological side effectsdisplayed by conventional neuroleptics. Compounds of the presentinvention demonstrate high affinity and selectivity in binding to the D₃receptor subtype. They may be of potential use in treatment ofschizophrenia, psychotic depression and mania. Other dopamine-mediateddiseases such as Parkinsonism and tardive dyskinesias may also betreated directly or indirectly by modulation of D₃ receptors.

U.S. Pat. No. 5,395,835 discloses N-aminoalkyl-2-napthalamides whichhave affinity at dopamine D₃ receptors. The compounds of the presentinvention differ significantly from this prior art in that they possessan anthracenecarboxamide substructure.

Murray et al., in Bioorg. Med. Chem. Let., 5: 219 (1995), describes4-carboxamido-biphenyls said to have affinity for dopamine D₃ receptors.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact withdopamine receptor subtypes. Thus, the invention provides compounds ofgeneral Formula I useful in the treatment and/or prevention of variousneuropsychological disorders. The invention also provides pharmaceuticalcompositions comprising compounds of Formula 1.

The invention further relates to the use of such compounds andcompositions in the treatment of affective disorders such asschizophrenia, depression, Alzheimer's disease and certain movementdisorders such as Parkinsonism and dystonia. Compounds of this inventionare also useful in treating the extrapyramidal side effects associatedwith the use of conventional neuroleptic agents. Further, the compoundsof the present invention are useful for the treatment of other disorderswhich respond to dopaminergic blockade such as substance abuse andobsessive compulsive disorder.

Since dopamine D₃ receptors are concentrated in the limbic system(Taubes, Science, 265: 1034 (1994)) which controls cognition andemotion, compounds which interact with these receptors also have utilityin the treatment of cognitive disorders. Such disorders includecognitive deficits which are a significant component of the negativesymptoms (social withdrawal and unresponsiveness) of schizophrenia.Other disorders involving memory impairment or attention deficitdisorders can also be treated with the compounds of this invention thatinteract specifically with the dopamine D₃ receptor subtype.

Furthermore, compounds of this invention may be useful in treatment ofdepression, memory-impairment or Alzheimer's disease by modulation of D₃receptors which selectively exist in limbic area known to controlemotion and cognitive functions. The compounds of the present inventionare also useful for the treatment of other disorders which respond todopaminergic blockade such as substance abuse (Caine and Koob, Science,260: 1814 (1993)) and obsessive compulsive disorder (Goodman et al.,Clin. Psychopharmacol., 7: 35 (1992)). The interaction of the compoundsof the invention with dopamine receptor subtypes is demonstrated below.This interaction results in the pharmacological activities of thesecompounds.

Accordingly, a broad embodiment of the invention is directed to acompound of Formula I: ##STR2## or the pharmaceutically acceptable acidaddition salts thereof, wherein: R₁ -R₉ are the same or different andrepresent hydrogen, C₁ -C₆ alkyl, halogen, hydroxy, amino, cyano, nitro,trifluoromethyl, trifluoromethoxy, C₁ -C₆ alkoxy, --O₂ CR', --NHCOR',--COR', --SO_(m) R", where R' is C₁ -C₆ alkyl and wherein m is 0, 1 or2; or

R₁ -R₉ independently represent --CONR'R", or --NR'R" where R' and R"independently represent hydrogen or C₁ -C₆ alkyl;

R₁₀ is hydrogen or C₁ -C₆ alkyl; and

R represents an aminoalkyl group.

Thus, the invention relates to the use of compounds of formula I in thetreatment and/or prevention of neuropsychochological disordersincluding, but not limited to, schizophrenia, mania, dementia,depression, anxiety, compulsive behavior, substance abuse, memoryimpairment, cognitive deficits, Parkinson-like motor disorders andmotion disorders related to the use of neuroleptic agents.

DETAILED DESCRIPTION OF THE INVENTION

In addition to compounds of general formula I described above, theinvention encompasses compounds of general formula IA: ##STR3## wherein:R₁ -R₁₀ are as defined above; and

R represents an aminoalkyl group of the formula ##STR4## where Arepresents an alkylene group of 2 to 6 carbon atoms optionallysubstituted with one or more alkyl groups having from 1 to 4 carbonatoms;

Z is N or C;

R₁₁ and R₁₂ are the same or different and represent hydrogen or C₁ -C₆alkyl; or

R₁₁ and R₁₂ together with the the 6-membered ring to which they areattached form a 5 to 8-membered ring, and

W is phenyl, naphthyl, 1-(5,6,7,8-tetrahydro)naphthyl or4-(1,2-dihydro)indenyl, pyridinyl, pyrimidyl, isoquinolinyl, quinolinyl,benzofuranyl, benzothienyl; each of which is optionally substituted withup to three groups independently selected from halogen, C₁ -C₆ alkyl, C₁-C₄ alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino,cyano, nitro, trifluoromethyl or trifluoromethoxy.

Preferred compounds of formula IA include those where R₁ -R₉ arehydrogen and A is alkylene of 3-5 carbon atoms.

In addition to compounds of general formula I described above, theinvention encompasses compounds of general formula IB: ##STR5## wherein:R₁ -R₁₂ are as defined above; and

A, Z and W are as defined above.

The present invention further encompasses compounds of Formula II:##STR6## wherein R₁ -R₁₂, A, and W are as defined above.

Preferred compounds of formula II are those where R₁ -R₉ are hydrogen; Ais C₃ -C₅ alkylene; and W is naphthyl or phenyl optionally substitutedwith up to three groups independently selected from halogen, C₁ -C₆alkyl, C₁ -C₄ alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino,dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy. Morepreferred compounds of formula II are those where R₁ -R₁₀ are hydrogen;A is C₃ -C₅ alkylene; and W is naphthyl or phenyl optionally substitutedwith up to two groups in the 2 and/or 3 and/or 6 positions (relative tothe point of attachment of the phenyl group to the piperazine ring), thegroups being independently selected from halogen, C₁ -C₄ alkyl, and C₁-C₄ alkoxy. Particularly preferred compounds of formula II are thosewhere R₁ -R₁₀ are hydrogen; A is C₄ alkylene; and W is naphthyl orphenyl optionally substituted with up to two groups in the 2 and/or 3and/or 6 positions (relative to the point of attachment of the phenylgroup to the piperazine ring), the groups being independently selectedfrom chloro, methyl, and methoxy.

The present invention further encompasses compounds of Formula III:##STR7## wherein R₁ -R₁₂, A, and W are as defined above.

Preferred compounds of formula III are those where R₁ -R₁₀ are hydrogen;A is C₃ -C₅ alkylene, more preferably butylene; and W is naphthyl orphenyl optionally substituted with up to three groups independentlyselected from halogen, C₁ -C₆ alkyl, C₁ -C₄ alkoxy, thioalkoxy, hydroxy,amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl ortrifluoromethoxy. Particularly preferred compounds of formula III arethose where R₁ -R₁₀ are hydrogen; A is C₃ -C₅ alkylene, more preferablybutylene; and W is phenyl or naphthyl.

The invention also provides compounds of Formula IV ##STR8## where R₁₀is hydrogen or C₁ -C₄ alkyl;

A represents alkylene group of 2 to 6 carbon atoms;

Z is nitrogen or carbon; and

W is phenyl or naphthyl, each of which is optionally substituted with upto three groups independently selected from halogen, C₁ -C₆ alkyl, C₁-C₄ alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino,cyano, nitro, trifluoromethyl or trifluoromethoxy.

Preferred compounds of formula IV are those where R₁₀ is hydrogen and Ais C₃ -C₅ alkylene. More preferred compounds of formula IV are thosewhere R₁₀ is hydrogen; A is C₄ alkylene; Z is nitrogen; and W isnaphthyl or phenyl optionally substituted with up to two groups in the 2and/or 3 and/or 6 positions (relative to the point of attachment of thephenyl group to the 6-membered nitrogen-containing ring), the groupsbeing independently selected from halogen, C₁ -C₄ alkyl, and C₁ -C₄alkoxy.

The invention also provides compounds of Formula V ##STR9## where R₁₀ ishydrogen or C₁ -C₄ alkyl;

A represents alkylene group of 2 to 6 carbon atoms; and

W is phenyl or naphthyl, each of which is optionally substituted with upto three groups independently selected from halogen, C₁ -C₆ alkyl, C₁-C₄ alkoxy, thioalkoxy, hydroxy, amino, monoallylamino, dialkylamino,cyano, nitro, trifluoromethyl or trifluoromethoxy.

Preferred compounds of formula V are those where R₁₀ is hydrogen and Ais C₃ -C₅ alkylene. More preferred compounds of formula V are thosewhere R₁₀ is hydrogen; A is C₄ alkylene; and W is naphthyl or phenyloptionally substituted with up to two groups in the 2 and/or 3 positionsand/or 6 positions (relative to the point of attachment of the phenylgroup to the 6-membered nitrogen-containing ring), the groups beingindependently selected from halogen, C₁ -C₄ alkyl, and C₁ -C₄ alkoxy.

The invention also provides compounds of Formula VI ##STR10## where R₁₀is hydrogen or C₁ -C₄ alkyl;

A represents alkylene group of 2 to 6 carbon atoms; and

W is phenyl or naphthyl, each of which is optionally substituted with upto three groups independendy selected from halogen, C₁ -C₆ alkyl, C₁ -C₄alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano,nitro, trifluoromethyl or aifluoromethoxy.

Preferred compounds of formula VI are those where R₁₀ is hydrogen and Ais C₃ -C₅ alkylene. More preferred compounds of formula VI are thosewhere R₁₀ is hydrogen; A is C₄ alkylene; and W is naphthyl or phenyloptionally substituted with up to two groups in the 2 and/or 3 positionsand/or 6 positions (relative to the point of attachment of the phenylgroup to the 6-membered nitrogen-containing ring), the groups beingindependently selected from halogen, C₁ -C₄ alkyl, and C₁ -C₄ alkoxy.

When a compound of the invention is obtained as a mixture ofenantiomers, these enantiomers may be separated, when desired, byconventional methods such as crystallization in the presence of aresolving agent, or chromatography, for example using a chiral HPLCcolumn.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in Table 1and their pharmaceutically acceptable salts. The present invention alsoencompasses prodrugs, e.g., acylated prodrugs, of the compounds ofFormula I. Those skilled in the art will recognize various syntheticmethodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and prodrugs of the compoundsencompassed by Formula I.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in Table 1and their pharmaceutically acceptable salts. Non-toxic pharmaceuticallyacceptable salts include salts of acids such as hydrochloric,phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic,methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic,alkanoic such as acetic, HOOC--(CH₂)_(n) --COOH where n is 0-4, and thelike. Those skilled in the art will recognize a wide variety ofnon-toxic pharmaceutically acceptable addition salts.

The following numbering system is used to identify positions on theanthracenecarboxamide portion of the compounds of the invention:##STR11##

By "alkyl" and "lower alkyl" is meant straight and branched chain alkylgroups having from 1-6 carbon atoms, e.g., C₁ -C₆ alkyl.

By "lower alkoxy" and "alkoxy" is meant straight and branched chainalkoxy groups having from 1-6 carbon atoms, e.g., C₁ -C₆ alkoxy.

By halogen is meant fluorine, chlorine, bromine and iodine.

The amino portion of the aminoalkyl group represented by R aboveincludes groups represented by the formula Q ##STR12## where W isdefined above.

Th formula Q represents saturated heterocyclic ring systems such as, forexample, piperidinyl and piperazinyl, as well as unsaturatedheterocyclic ring systems such as, for example, 1, 2, 3,6-tetrahydropyrindine. Preferred Q groups are the following: ##STR13##where W is defined above.

Particularly preferred W groups of the invention are phenyl optionallysubstituted with up to two substituents independently selected fromhalogen, C₁ -C₄ alkyl, and C₁ -C₄ alkoxy. These optional phenylsubstituents are preferably in the 2 and/or 3 and/or 6 positions of thephenyl group relative to the point of attachment of the phenyl group tothe 6-membered nitrogen containing ring.

Representative examples of N-Aminoalkylanthracenecarboxamides accordingto the invention are shown in Table 1 below. The number below eachcompound is its compound number. Each of these compounds may be preparedaccording to the general reaction Scheme I set forth below.

The compounds in Table 1 have the following general formula A: ##STR14##where R and R₁₀ are defined in the table.

                  TABLE 1    ______________________________________    Comound    Number R.sub.5                  R    ______________________________________    1      H                   ##STR15##    2      H                   ##STR16##    3      H                   ##STR17##    4      H                   ##STR18##    5      H                   ##STR19##    6      H                   ##STR20##    7      H                   ##STR21##    ______________________________________

Particular compounds according to the invention include:

N-{4-4-(2,3-Dichlorophenyl)-1-piperazinyl!butyl}-2-anthracenecarboxamidehydrochloride

N-{4- 4-(1-Naphthyl)-1-piperazinyl!butyl }-2-anthracenecarboxamidehydrochloride

N-{4-4-(2,3-Dimethylphenyl)-1-piperazinyl!butyl}-2-anthracenecarboxamidehydrochloride

N-{4- 4-(2-Methylphenyl)-1-piperazinyl!butyl}-2-anthracenecarboxamidehydrochloride

N-{4- 4-(2-Chlorophenyl)-1-piperazinyl!butyl}-2-anthracenecarboxamidehydrochloride

N-{4- 4-(2-Methoxyphenyl)-1-piperazinyl!butyl}-2-anthracenecarboxamidehydrochloride

N-{4- 4-(8-Isoquinolinyl)-1-piperazinyl!butyl}-2-anthracenecarboxamidehydrochloride

N-{4-4-Phenyl-1-(1,2,3,6-tetrahydropyridinyl)!butyl}-2-anthracenecarboxamidehydrochloride

N-{4-4-(3-Chloro-2-methylphenyl)-1-piperazinyl!butyl}-2-anthracenecarboxamidehydrochloride

N-{4-4-(1-Naphthyl)-1-(1,2,3,6-tetrahydropyridinyl)!butyl}-2-anthracenecarboxamidehydrochloride

N-{4- 4-Phenyl-1-piperidinyl)!butyl}-2-anthracenecarboxamidehydrochloride

The invention also pertains to the use of compounds of general Formula Iin the treatment of neuropsychological disorders. The pharmaceuticalutility of compounds of this invention are indicated by the followingassays for dopamine receptor subtype affinity.

ASSAY FOR D₂ AND D₃ RECEPTOR BINDING ACTIVITY

Pellets of COS cells containing recombinantly produced D₂ or D₃receptors from African Green monkey were used for the assays. The sampleis homogenized in 100 volumes (w/vol) of 0.05M Tris HCl buffer at 4° C.and pH 7.4. The sample is then centrifuged at 30,000×g and resuspendedand rehomogenized. The sample is then centrifuged as described and thefinal tissue sample is frozen until use. The tissue is resuspended 1:20(wt/vol) in 0.05M Tris HCl buffer containing 100 mM NaCl.

Incubations are carried out at 48° C. and contain 0.4 ml of tissuesample, 0.5 nM ³ H-YM 09151-2 and the compound of interest in a totalincubation of 1.0 ml. Nonspecific binding is defined as that bindingfound in the presence of 1 mM spiperone; without further additions,nonspecific binding is less than 20% of total binding. The bindingcharacteristics of representative compounds of the invention for D₂ andD₃ receptor subtypes are shown in Table 2 for rat striatal homogenates.

                  TABLE 2    ______________________________________    Compound Number.sup.1                     D.sub.3 K.sub.i (nM)                              D.sub.2 K.sub.i (nM)    ______________________________________    1                7        1089    2                1.2      550    ______________________________________     .sup.1 Compound numbers relate to compounds shown above in Table 1.

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalFormula I and a pharmaceutically acceptable carrier. One or morecompounds of general Formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general Formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropyl methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidpaaaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe and partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitor or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general Formula I may also be administered in the formof suppositories for rectal admiinistration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

Preparation of N-Aminoalkylanthracenecarboxamides

The compounds of Formula I, and the pharmaceutically acceptable acidaddition salts thereof, may be prepared according to the reactions shownbelow in Scheme 1. ##STR22## wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉,R₁₀, R₁₁, R₁₂, A, Z and W are as defined above for Formula IA.

As shown, a compound of Formula VII may be activated by1,1'-carbonyldiimidazole (CDI) or thionyl chloride (SOCl₂) or the likein solvents such as tetrahydrofuran or dichloromethane at roomtemperature. The resulting activated species may be subsequently reactedwith the required compound of Formula VIII to afford a compound ofFormula I as the desired product.

Where they are not commercially available, the compounds of Formula VIImay be prepared by literature procedures or procedures analogous tothose described in literature. The compounds of Formula VIII are eitherknown or capable of being prepared by various methods known in the art.

Those having skill in the art will recognize that the starting materialsmay be varied and additional steps employed to produce compoundsencompassed by the present invention, as demonstrated by the followingexamples. In some cases protection of certain reactive functionalitiesmay be necessary to achieve some of the above transformations. Ingeneral the need for such protecting groups will be apparent to thoseskilled in the art of organic synthesis as well as the conditionsnecessary to attach and remove such groups.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures described in them. These examples illustrate thepresently preferred methods for preparing the compounds of theinvention.

EXAMPLE 1 ##STR23## N-{4-4-(2,3-Dichlorophenyl)-1-piperazinyl!butyl}-2-anthracenecarboxamide

A mixture of 2-anthracenecarboxylic acid (100 mg, 0.45 mmol) and1,1'-carbonyldiimidazole (82 mg, 0.5 mmol) in 10 mL of anhydroustetrahydrofuran is stirred for 8 hours. A solution of 4-4-(2,3-dichlorophenyl)-1-piperazinyl!-1-aminobutane (150 mg, 0.5 mmol)in 1 mL of tetrahydrofuran is added and the resulting mixture is stirredfor 30 minutes. The reaction mixture is partitioned between ethylacetate and water. The organic layer is washed with aqueous Na₂ CO₃,dried (Na₂ SO₄) and concentrated in vacuo to give the title compound(183 mg, 80%). The hydrochloride salt is prepared by treating the freebase with ethyl acetate-HCl. The hydrochloride salt of the titlecompound has a melting point of 245°-247° C.

EXAMPLE 2

The following compounds of Formula 1 are prepared essentially accordingto the procedures set forth in Example 1 above.

(a) N-{4- 4-(1-Naphthyl)-1-piperazinyl!butyl}-2-anthracenecarboxamidehydrochloride (mp 236°-238° C.)

(b) N-{4-4-(2,3-Dimethylphenyl)-1-piperazinyl!butyl}-2-anthracenecarboxamidehydrochloride (mp 244°-246° C.)

(c) N-{4-4-(2-Methylphenyl)-1-piperazinyl!butyl}-2-anthracenecarboxamidehydrochloride (mp 213°-215° C.)

(d) N-{4-4-(2-Chlorophenyl)-1-piperazinyl!butyl}-2-anthracenecarboxamidehydrochloride (mp 218°-220° C.)

(e) N-{4-4-(2-Methoxyphenyl)-1-piperazinyl!butyl}-2-anthracenecarboxamidedihydrochloride (mp 253°-255° C.)

(f) N-{4-4-(8-Isoquinolinyl)-1-piperazinyl!butyl}-2-anthracenecarboxamidedihydrochloride (mp 235°-237° C.)

(g) N-{4-4-Phenyl-1-(1,2,3,6-tetrahydropyridinyl!butyl}-2-anthracenecarboxamidehydrochloride (mp 248°-250° C.)

(h) N-{4-4-(3-Chloro-2-methylphenyl)-1-piperazinyl!butyl}-2-anthracenecarboxamidedihydrochloride (mp 247°-249° C.)

(i) N-{4-4-(1-Naphthyl)-1-(1,2,3,6-tetrahydropyridinyl)!butyl}-2-anthracenecarboxamidehydrochloride (mp 233°-236° C.)

(j) N-{4- 4-Phenyl-1-piperidinyl)!butyl}-2-anthracenecarboxamidehydrochloride (mp 225°-227° C.)

What is claimed is:
 1. A compound of the formula: ##STR24## or thepharmaceutically acceptable salts thereof wherein: R₁, R₂, R₃, R₄, R₅,R₆, R₇, R₈ and R₉ are the same or different and represent hydrogen, C₁-C₆ alkyl, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl,trifluoromethoxy, C₁ -C₆ alkoxy, --O₂ CR', --NHCOR', --COR', --SO_(m)R', where R' is C₁ -C₆ alkyl and wherein m is 0, 1 or 2; orR₁, R₂, R₃,R₄, R₅, R₆, R₇, R₈ and R₉ independently represent --CONR'R", or --NR'"where R' and R" independently represent hydrogen or C₁ -C₆ alkyl; R₁₀ ishydrogen or C₁ -C₆ alkyl; and R represents an aminoalkyl group of theformula ##STR25## where A represents an alkylene group of 2 to 6 carbonatoms optionally substituted with one or more alkyl groups having from 1to 4 carbon atoms;R₁₁ and R₁₂ are the same or different and representhydrogen or C₁ -C₆ alkyl; and W is phenyl, naphthyl,1-(5,6,7,8-tetrahydro)naphthyl or 4-(1,2-dihydro)indenyl, pyridinyl,pyrimidyl, isoquinolinyl, quinolinyl, benzofuranyl, benzothienyl; eachof which is optionally substituted with up to three groups independentlyselected from halogen, C₁ -C₆ alkyl, C₁ -C₄ alkoxy, thioalkoxy, hydroxy,amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl ortrifluoromethoxy.
 2. A compound of the formula: ##STR26## wherein: R₁,R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are the same or different andrepresent hydrogen, C₁ -C₆ alkyl, halogen, hydroxy, amino, cyano, nitro,trifluoromethyl, trifluoromethoxy, C₁ -C₆ alkoxy, --O₂ CR', --NHCOR',--COR', SO_(m) R', where R' is C₁ -C₆ alkyl and wherein m is 0, 1 or 2;orR₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ independently represent--CONR'R", or --NR'R" where R' and R" independently represent hydrogenor C₁ -C₆ alkyl; R₁₀ is hydrogen or C₁ -C₆ alkyl; and A represents analkylene group of 2 to 6 carbon atoms optionally substituted with one ormore alkyl groups having from 1 to 4 carbon atoms; Z is C; R₁₁ and R₁₂are hydrogen and W is phenyl, naphthyl, 1-(5,6,7,8-tetrahydro)naphthylor 4-(1,2-dihydro)indenyl, pyridinyl, pyrimidyl, quinolinyl,isoquinolinyl, benzofuranyl, benzothienyl; each of which is optionallysubstituted with up to three groups independently selected from halogen,C₁ -C₆ alkyl, C₁ -C₄ alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino,dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy.
 3. Acompound according to claim 1 which is ##STR27## wherein R₁₁ and R₁₂ arethe same or different and represent hydrogen or C₁ -C₆ alkyl; andArepresents an alkylene group of 2 to 6 carbon atoms optionallysubstituted with one or more alkyl groups having from 1 to 4 carbonatoms; and W is phenyl, naphthyl, 1-(5,6,7,8-tetrahydro)naphthyl or4-(1,2-dihydro)indenyl, pyridinyl, pyrimidyl, quinolinyl, isoquinolinyl,benzofuranyl, benzothienyl; each of which is optionally independentlysubstituted with up to three groups selected from halogen, C₁ -C₆ alkyl,C₁ -C₄ alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino,cyano, nitro, trifluoromethyl or trifluoromethoxy.
 4. A compound of theformula: ##STR28## wherein: R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ arethe same or different and represent hydrogen, C₁ -C₆ alkyl, halogen,hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C₁ -C₆alkoxy, --O₂ CR', --NHCOR', --COR', --SO_(m) R', where R' is C₁ -C₆alkyl and wherein m is 0, 1 or 2; orR₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ andR₉ independently represent --CONR'R", or --NR'R" where R' and R"independently represent hydrogen or C₁ -C₆ alkyl; R₁₀ is hydrogen or C₁-C₆ alkyl; and A represents an alkylene group of 2 to 6 carbon atomsoptionally substituted with one or more alkyl groups having from 1 to 4carbon atoms; R₁₁ and R₁₂ are the same or different and representhydrogen or C₁ -C₆ alkyl; and W is phenyl, naphthyl,1-(5,6,7,8-tetrahydro)naphthyl or 4-(1,2-dihydro)indenyl, pyridinyl,pyrimidyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl; eachof which is optionally substituted with up to three groups independentlyselected from halogen, C₁ -C₆ alkyl, C₁ -C₄ alkoxy, thioalkoxy, hydroxy,amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl ortrifluoromethoxy.
 5. A compound according to claim 4, wherein R₁ -R₉ arehydrogen; R₁₁ and R₁₂ are hydrogen; A is C₃ -C₅ alkylene; and W isnaphthyl or phenyl optionally substituted with up to three groupsindependently selected from halogen, C₁ -C₆ alkyl, C₁ -C₄ alkoxy,thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro,trifluoromethyl or trifluoromethoxy.
 6. A compound according to claim 4,wherein R₁ -R₁₀ are hydrogen; R₁₁ and R₁₂ are hydrogen; A is C₃ -C₅alkylene; and W is naphthyl or phenyl optionally substituted with up totwo groups in the 2 and/or 3 and/or 6 positions, the groups beingindependently selected from halogen, C₁ -C₄ alkyl, and C₁ -C₄ alkoxy. 7.A compound according to claim 4, wherein R₁ -R₁₀ are hydrogen; R₁₁ andR₁₂ are hydrogen; A is C₄ alkylene; and W is naphthyl or phenyloptionally substituted with up to two groups in the 2 and/or 3 and/or 6positions, the groups being independently selected from chloro, methyl,and methoxy.
 8. A compound according to claim 1, which is N-{4-4-Phenyl-1-(1,2,3,6-tetrahydropyridinyl)!butyl}-2-anthracenecarboxamide.9. A compound according to claim 1, which is N-{4- 4-(1-Naphthyl)-1-(1,2,3,6-tetrahydropyridinyl)!butyl}-2-anthracenecarboxamide.
 10. Acompound according to claim 1, which is N-{4-4-Phenyl-1-piperidinyl)!butyl}-2-anthracenecarboxamide.
 11. A compoundaccording to claim 1, which is N-{4-4-Phenyl-1-(1,2,3,6-tetrahydropyridinyl)!butyl}-2-anthracenecarboxamidehydrochloride.
 12. A compound according to claim 1, which is N-{4-4-(1-Naphthyl)-1-(1,2,3,6-tetrahydropyridinyl)!butyl}-2-anthracenecarboxamidehydrochloride.
 13. A compound according to claim 1, which is N-{4-4-Phenyl-1-piperidinyl)!butyl}-2-anthracenecarboxamide hydrochloride.